Aripiprazole for treating moderate to severe manic episodes in adolescents with bipolar I disorder

3 The manufacturer's submission

The Appraisal Committee (section 8) considered evidence submitted by the manufacturer of aripiprazole and a review of this submission by the Evidence Review Group (ERG; section 9).

3.1 The manufacturer presented direct clinical-effectiveness evidence from 2 randomised controlled trials comparing aripiprazole with placebo and performed a meta-analysis of these trials. The manufacturer also presented a network meta-analysis based on a network containing aripiprazole, olanzapine, risperidone, quetiapine and placebo.

3.2 The manufacturer undertook a systematic review to identify published evidence for aripiprazole for the treatment and prevention of acute manic and mixed episodes in children and adolescents with bipolar disorder. The review identified 3 randomised controlled trials (NCT00110461, NCT00194077 and NCT00116259) that investigated aripiprazole in children and adolescents with bipolar disorder. The NCT00194077 trial was excluded because it only included children under the age of 10, a group outside the licensed indication. The manufacturer considered NCT00110461 to be the main evidence for the use of aripiprazole in children and adolescents. The NCT00116259 trial was not discussed in detail because the manufacturer considered it to be a small trial in a specific population of children and adolescents with bipolar disorder (both types I and II) and attention-deficit hyperactive disorder (ADHD). No relevant non-randomised controlled trial evidence for aripiprazole was identified from the systematic review.

3.3 NCT00110461 was a multicentre, double-blind, randomised, placebo-controlled clinical trial undertaken across 59 sites in the USA between March 2005 and February 2007. The study was designed to test the safety and efficacy of 2 doses of aripiprazole in children and adolescents with bipolar I disorder who experienced manic or mixed episodes with or without psychotic features. There were 296 participants randomised to receive aripiprazole 10 mg/day (n=98), aripiprazole 30 mg/day (n=99) or placebo (n=99). The study duration was 30 weeks with a 4-week acute phase followed by an extension phase of 26 weeks.

3.4 Participants in NCT00110461 were aged between 10 and 17 years with a DSM-IV diagnosis of bipolar I disorder who were experiencing manic or mixed episodes, with or without psychotic features. Comorbid diagnoses were permitted including ADHD, conduct disorder, oppositional defiant disorder and anxiety disorders. All participants had a baseline Young Mania Rating Scale (YMRS) score of more than 20. Exclusion criteria included bipolar II disorder, unspecified bipolar disorder and psychosis caused by other medical conditions or concomitant mediations. Participants with learning disabilities and those who were determined by the investigator to be at risk of suicide were also excluded.

3.5 In the NCT00110461 trial, 72% (296/413) of participants screened were enrolled in the study. Participant characteristics at baseline were comparable between the 3 groups in the trial. Approximately 63% of participants were aged 13 or over and fell within the licensed population. In response to a clarification request, the manufacturer provided post-hoc data on the proportion of participants in mixed and manic states at baseline and on the proportion of 'rapid cyclers' (participants who experienced 4 or more manic, hypomanic or mixed episodes in the previous year). In both cases the proportions were relatively similar between the groups.

3.6 The primary outcome in NCT00110461 was the change from baseline to week 4 on the YMRS total score. Secondary outcomes were changes from baseline scores in the Children's Global Assessment Scale (CGAS), Clinical Global Impressions Scale-Bipolar Version (CGI-BP) severity scores for mania, depression and overall bipolar illness, Children's Depression Rating Scale - Revised (CDRS-R) score, General Behaviour Inventory Scale (GBI) score and Attention-Deficit Hyperactivity Disorders Rating Scale (ADHD-RS-IV) score. A YMRS response rate was based on a responder definition of a 50% or more reduction from the YMRS total score at baseline.

3.7 In the NCT00110461 trial, both aripiprazole doses demonstrated statistically significant improvements over placebo in the YMRS total score at week 4, with treatment differences from placebo of −5.99 (95% confidence interval −8.49 to −3.50; p<0.0001) for the aripiprazole 10 mg group, and −8.26 (95% CI −10.7 to −5.77; p<0.0001) for the aripiprazole 30 mg group. Statistically significant improvements in YMRS total score were demonstrated at week 1 for both aripiprazole doses, and were maintained until week 30. At week 30, the treatment difference in YMRS total score from placebo for the aripiprazole 10 mg dose was −5.89 (95% CI −8.70 to −3.08), and for the aripiprazole 30 mg dose it was −6.73 (95% CI −9.53 to −3.94). The YMRS responder rates were also significantly higher in the aripiprazole arms than in the placebo arm at week 4 and week 30.

3.8 Both aripiprazole doses demonstrated significant improvements at week 4 compared with baseline in the secondary end points: CGAS core, CGI-BP severity scores for mania, depression and overall bipolar illness, GBI – parent/guardian version and subject version mania total score, and the ADHD-RS-IV total score. Significant differences were not observed at week 4 in the CGI-BP severity scores for depression, GBI – patient depression total scores or the CDRS-R score. A significant difference was observed in the 10 mg aripiprazole arm for the GBI-parent/guardian version for depression (p= 0.0430) but not in the 30 mg arm.

3.9 The manufacturer presented results from a post-hoc subgroup analysis based on the change in YMRS score from baseline calculated using both the observed case dataset and the last observation carried forward dataset for age subgroups (10–12, and 13–17 years). Results from the last observation carried forward data showed that participants receiving aripiprazole in both age groups had a statistically significant change in YMRS score from baseline at both weeks 4 and 12 compared with those receiving placebo. Using the observed case dataset, there was a statistically significant change in YMRS score in participants receiving aripiprazole in both age groups at week 4; however by week 12, although the change in YRMS score was still greater in participants receiving aripiprazole compared with those receiving placebo, this was not statistically significant.

3.10 At the end of the acute phase of the trial (4 weeks) the proportion of participants not completing the trial was 14.3% in the aripiprazole 10 mg group, 22.2% in the aripiprazole 30 mg group and 23.2% in the placebo group. At 30 weeks the drop-out rates were 65.3% in the aripiprazole 10 mg group, 77.7% in the aripiprazole 30 mg group and 87.9% in the placebo group. The manufacturer noted the statement in the Committee for Medicinal Products for Human Use (CHMP) assessment report that results based on the observed case analysis dataset failed to show statistical significance for aripiprazole compared with placebo for both doses on all analysed efficacy end points at week 12. The manufacturer stated that the lack of statistically significant differences between aripiprazole and placebo at week 12 along with the high discontinuation rate resulted in the CHMP restricting the treatment length with aripiprazole to 12 weeks.

3.11 The manufacturer also carried out a post-hoc subgroup analysis to investigate if the efficacy of aripiprazole was influenced by the presence or absence of ADHD symptoms. Results presented in 3 age subgroups (10–12, 13–14, and 15–17 years) suggested no change in the treatment effect.

3.12 In NCT00110461, health-related quality of life was measured by the Pediatric Quality of Life Enjoyment and Satisfaction Questionnaire (PQ-LES-Q). The manufacturer reported that although the results did not reach statistical significance, both aripiprazole arms demonstrated a trend for improvement relative to placebo.

3.13 The manufacturer presented adverse events occurring in more than 5% of any group in NCT00110461 over the acute phase and over the full trial duration. There were no deaths or suicides in the study. The manufacturer acknowledged that somnolence and extrapyramidal symptoms occurred more frequently in the aripiprazole arms than in the placebo group. In the acute phase (up to 4 weeks) extrapyramidal disorder occurred in 12.2% (12/98) of the aripiprazole 10 mg group, 27.3% (27/99) of the aripiprazole 30 mg group and 3.1% (3/97) of the placebo group. In the acute phase (up to 4 weeks) somnolence occurred in 19.4% (19/98) of the aripiprazole 10 mg group, 26.3% (26/99) of the aripiprazole 30 mg group and 3.1% (3/97) of the placebo group. In the acute phase (up to 4 weeks) akathisia occurred in 8.2% (8/98) of the aripiprazole 10 mg group, 11.1% (11/99) of the aripiprazole 30 mg group and 2.1% (2/97) of the placebo group. The manufacturer concluded that most of the adverse events occurred in the acute phase of the study and were mild to moderate in severity, and therefore were expected to be manageable.

3.14 The manufacturer presented changes in baseline metabolic parameters at 4 and 30 weeks. Differences in the treatment groups between the incidence of clinically significant weight gain (7% or more weight gain compared with baseline) and change from baseline body mass index (BMI) were not statistically significant at week 4. Data on the incidence of clinically significant weight gain at 30 weeks was considered to be academic in confidence by the manufacturer and therefore cannot be reported in this document. There were no differences between the treatment groups in the proportion of participants with a BMI on or above the 95th percentile for age and sex at week 4. Data on the proportion of participants with a BMI on or above the 95th percentile at week 30 was considered to be academic in confidence.

3.15 The manufacturer noted that the CHMP limited the indication for aripiprazole to adolescents aged 13 and over as a result of safety concerns in younger people. The manufacturer reported results from a post-hoc subgroup analysis to assess the safety profile across age subgroups (10–12 years, and 13–17 years). In the 10–12 years subgroup there were statistically significant increases in mean weight and BMI changes from baseline in the aripiprazole 30 mg treatment arm at weeks 4 and 12. There were also statistically significant increases in weight and BMI measurements in the aripiprazole 10 mg treatment arm at week 12 using the last observation carried forward analysis for the 10–12 years subgroup.

3.16 The NCT00116259 trial was a double-blind randomised placebo-controlled clinical trial undertaken in Brazil. There were 43 participants who were randomised to receive aripiprazole 20 mg per day (n=18) or placebo (n=25). The study duration was 6 weeks. Participants were aged between 8 and 17 years with a DSM-IV diagnosis of bipolar I or II disorder, comorbid with DSM-IV ADHD. All participants were in an acutely manic or mixed state defined as a YMRS score of more than 20 at the baseline visit. Exclusion criteria included learning disabilities and severe risk of suicide.

3.17 Results from NCT00116259 showed that participants receiving aripiprazole had a statistically significantly larger reduction in YMRS total scores from baseline to week 6 than participants receiving placebo (−27.22 versus −19.52, p=0.02). A greater proportion of participants on aripiprazole compared with placebo experienced a response (88.9% versus 52%, p=0.02; number needed to treat [NNT] =2.70) and experienced remission (72% versus 32%, p=0.01; NNT=2.50).

3.18 The manufacturer presented a meta-analysis of NCT00110461 (pooled 10 mg per day and 30 mg per day) and NCT00116259 (20 mg per day). Results from the meta-analysis indicated that aripiprazole was statistically significantly superior to placebo in inducing symptomatic response (as measured as a 50% or more change in YMRS score) at weeks 1, 2 and 4, but not at week 3. Also, results from the meta-analysis showed aripiprazole to be associated with a statistically significant higher rate of extrapyramidal symptoms than placebo, but not of somnolence. The manufacturer commented that the meta-analysis was performed to be transparent rather than to provide meaningful results. The manufacturer stated that the results should be treated with caution because the information from the NCT00116259 trial is limited by the small trial size and the different population compared with NCT00110461 (that is, it included people with bipolar II disorder and was restricted to participants with comorbid ADHD).

3.19 As there are no head-to-head trials comparing aripiprazole with the comparators specified in the final scope issued by NICE, the manufacturer presented a network meta-analysis to determine the relative efficacy of the treatments using placebo as the common comparator. Five randomised controlled trials were identified in addition to the 2 studies including aripiprazole (NCT00110461 and NCT00116259). The 5 studies were as follows: 3 studies for risperidone (risperidone compared with placebo, risperidone compared with divalproex sodium [valproate semisodium] and risperidone compared with divalproex sodium and lithium), 1 study for quetiapine (quetiapine compared with placebo), and 1 study for olanzapine (olanzapine compared with placebo). The network meta-analysis included NCT00110461, one of the studies for risperidone (risperidone compared with placebo), and the studies for quetiapine and olanzapine (both compared with placebo). The manufacturer undertook a sensitivity analysis in which the NCT00116259 trial and the remaining 2 studies for risperidone (risperidone compared with lithium and divalproex sodium) were also included.

3.20 The network analysis used a fixed-effects Bayesian model, because the manufacturer considered there was not enough evidence to support the estimation of a random-effects model. Results from studies that included treatment groups with different intervention doses were pooled to provide an average treatment dose effect. Efficacy outcomes considered in the network meta-analysis were the YMRS response rates at weeks 1, 2 and 3, and discontinuation at week 3. Analyses were also conducted for the following safety outcomes: extrapyramidal symptoms, clinically significant weight gain, clinically significant increase in prolactin and somnolence.

3.21 The manufacturer presented results from the network meta-analysis as relative risks using placebo and aripiprazole (pooled dose) as references. These results indicated that all the antipsychotics considered (aripiprazole, risperidone, quetiapine and olanzapine) were statistically more effective than placebo at achieving YMRS response at weeks 1–3. The results also indicated that there were no statistically significant differences in YMRS response rates at weeks 1–3 between the antipsychotics. No statistically significant differences were found for discontinuation of treatment at week 3 between the interventions considered in the network.

3.22 Participants receiving aripiprazole were found to be statistically significantly more likely to experience extrapyramidal symptoms than those receiving placebo. They were also more likely to experience them than participants receiving risperidone and quetiapine, but these differences were not statistically significant. There was no statistically significant difference between aripiprazole and placebo in the risk of experiencing a clinically significant increase in weight. Aripiprazole (pooled dose) was statistically significantly less likely to cause clinically significant weight gain than olanzapine and quetiapine. Participants receiving aripiprazole were less likely to experience a clinically significant increase in prolactin than those on olanzapine, risperidone or quetiapine. Participants receiving aripiprazole were found to be statistically significantly more likely to experience somnolence than those receiving placebo. They were also more likely to experience somnolence than participants receiving risperidone and quetiapine, but this was not statistically significant.